We propose to develop a soluble, DNA carrier system that can target foreign genes specifically to hepatocytes. The idea is based on: 1) The presence of unique cell-surface receptors on hepatocytes that can internalize galactose-terminal (asialo-) glycoproteins 2) polycations can form strong, non-covalent interactions with DNA resulting in the formation of soluble complexes. We hypothesized that chemical coupling of an asialoglycoprotein to a polycation could result in a conjugate that, upon subsequent exposure to DNA could form a soluble complex which then could be targeted specifically to hepatocytes via their asialoglycoprotein receptors. To test the idea, we propose to synthesize various asialoglycoprotein- polycation conjugates and screen them for: 1) DNA binding by an agarose gel retardation system, asialoglycoprotein rector recognition using an in vitro uptake assay, targeted using an assay for CAT enzyme activity in vitro. Conjugates will be tested in normal rats to identify the most effective conjugate for liver-specific targeted gene delivery and expression in vivo. The efficiency of hepatic delivery of intact foreign sequences will be determined by Southern blot; histological distribution of targeted DNA by in situ hybridization, and localization of actual foreign product by immunofluorescence. We determine the time course and examine the effects of enzyme inhibitors and lysosomotropic amines on the efficiency of targeted gene expression. Several methods for stimulation hepatocyte regeneration (partial hepatectomy, CCl4 and nafenopin) will be studied to enhance persistence of targeted gene expression in vivo. Finally, we propose to prepare plasmids containing the human albumin structural gene driven by natural albumin, or viral regulatory elements. Using a mutant (Nagase NAR) strain of rats genetically deficient in the production of serum albumin, the soluble DNA carrier system will be tested for its ability to deliver these plasmids and correct the inherited disorder of metabolism by intravenous injection.